Structure‐based identification of dual ligands at the A2AR and PDE10A with anti‐proliferative effects in lung cancer cell‐lines
Abstract Enhanced/prolonged cAMP signalling has been suggested as a suppressor of cancer proliferation. Interestingly, two key modulators that elevate cAMP, the A2A receptor (A2AR) and phosphodiesterase 10A (PDE10A), are differentially co-expressed in various types of non-small lung cancer (NSCLC) c...
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| Format: | Article |
| Language: | English |
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BMC
2021-03-01
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| Series: | Journal of Cheminformatics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13321-021-00492-5 |
| _version_ | 1818556510562680832 |
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| author | Leen Kalash Ian Winfield Dewi Safitri Marcel Bermudez Sabrina Carvalho Robert Glen Graham Ladds Andreas Bender |
| author_facet | Leen Kalash Ian Winfield Dewi Safitri Marcel Bermudez Sabrina Carvalho Robert Glen Graham Ladds Andreas Bender |
| author_sort | Leen Kalash |
| collection | DOAJ |
| description | Abstract Enhanced/prolonged cAMP signalling has been suggested as a suppressor of cancer proliferation. Interestingly, two key modulators that elevate cAMP, the A2A receptor (A2AR) and phosphodiesterase 10A (PDE10A), are differentially co-expressed in various types of non-small lung cancer (NSCLC) cell-lines. Thus, finding dual-target compounds, which are simultaneously agonists at the A2AR whilst also inhibiting PDE10A, could be a novel anti-proliferative approach. Using ligand- and structure-based modelling combined with MD simulations (which identified Val84 displacement as a novel conformational descriptor of A2AR activation), a series of known PDE10A inhibitors were shown to dock to the orthosteric site of the A2AR. Subsequent in-vitro analysis confirmed that these compounds bind to the A2AR and exhibit dual-activity at both the A2AR and PDE10A. Furthermore, many of the compounds exhibited promising anti-proliferative effects upon NSCLC cell-lines, which directly correlated with the expression of both PDE10A and the A2AR. Thus, we propose a structure-based methodology, which has been validated in in-vitro binding and functional assays, and demonstrated a promising therapeutic value. |
| first_indexed | 2024-12-13T23:48:16Z |
| format | Article |
| id | doaj.art-475f56f41ee54ebda841325ad9547893 |
| institution | Directory Open Access Journal |
| issn | 1758-2946 |
| language | English |
| last_indexed | 2024-12-13T23:48:16Z |
| publishDate | 2021-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Cheminformatics |
| spelling | doaj.art-475f56f41ee54ebda841325ad95478932022-12-21T23:26:52ZengBMCJournal of Cheminformatics1758-29462021-03-0113111710.1186/s13321-021-00492-5Structure‐based identification of dual ligands at the A2AR and PDE10A with anti‐proliferative effects in lung cancer cell‐linesLeen Kalash0Ian Winfield1Dewi Safitri2Marcel Bermudez3Sabrina Carvalho4Robert Glen5Graham Ladds6Andreas Bender7Centre for Molecular Informatics, Department of Chemistry, University of CambridgeCentre for Molecular Informatics, Department of Chemistry, University of CambridgeDepartment of Pharmacology, University of CambridgeCentre for Molecular Informatics, Department of Chemistry, University of CambridgeDepartment of Pharmacology, University of CambridgeCentre for Molecular Informatics, Department of Chemistry, University of CambridgeDepartment of Pharmacology, University of CambridgeCentre for Molecular Informatics, Department of Chemistry, University of CambridgeAbstract Enhanced/prolonged cAMP signalling has been suggested as a suppressor of cancer proliferation. Interestingly, two key modulators that elevate cAMP, the A2A receptor (A2AR) and phosphodiesterase 10A (PDE10A), are differentially co-expressed in various types of non-small lung cancer (NSCLC) cell-lines. Thus, finding dual-target compounds, which are simultaneously agonists at the A2AR whilst also inhibiting PDE10A, could be a novel anti-proliferative approach. Using ligand- and structure-based modelling combined with MD simulations (which identified Val84 displacement as a novel conformational descriptor of A2AR activation), a series of known PDE10A inhibitors were shown to dock to the orthosteric site of the A2AR. Subsequent in-vitro analysis confirmed that these compounds bind to the A2AR and exhibit dual-activity at both the A2AR and PDE10A. Furthermore, many of the compounds exhibited promising anti-proliferative effects upon NSCLC cell-lines, which directly correlated with the expression of both PDE10A and the A2AR. Thus, we propose a structure-based methodology, which has been validated in in-vitro binding and functional assays, and demonstrated a promising therapeutic value.https://doi.org/10.1186/s13321-021-00492-5DockingMD simulationsStructure‐based designVirtual screeningA2ARPDE10A |
| spellingShingle | Leen Kalash Ian Winfield Dewi Safitri Marcel Bermudez Sabrina Carvalho Robert Glen Graham Ladds Andreas Bender Structure‐based identification of dual ligands at the A2AR and PDE10A with anti‐proliferative effects in lung cancer cell‐lines Journal of Cheminformatics Docking MD simulations Structure‐based design Virtual screening A2AR PDE10A |
| title | Structure‐based identification of dual ligands at the A2AR and PDE10A with anti‐proliferative effects in lung cancer cell‐lines |
| title_full | Structure‐based identification of dual ligands at the A2AR and PDE10A with anti‐proliferative effects in lung cancer cell‐lines |
| title_fullStr | Structure‐based identification of dual ligands at the A2AR and PDE10A with anti‐proliferative effects in lung cancer cell‐lines |
| title_full_unstemmed | Structure‐based identification of dual ligands at the A2AR and PDE10A with anti‐proliferative effects in lung cancer cell‐lines |
| title_short | Structure‐based identification of dual ligands at the A2AR and PDE10A with anti‐proliferative effects in lung cancer cell‐lines |
| title_sort | structure based identification of dual ligands at the a2ar and pde10a with anti proliferative effects in lung cancer cell lines |
| topic | Docking MD simulations Structure‐based design Virtual screening A2AR PDE10A |
| url | https://doi.org/10.1186/s13321-021-00492-5 |
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